Glucagon is a polypeptide hormone secreted by the alpha cells of the Islets of Langerhans in the pancreas. In native form it is a single chain polypeptide of 29 amino acid residues, the sequence of which is provided in Merck Index 10th Edition (1983).
Physiologically, glucagon plays a major role in the regulation of blood glucose levels and is involved in glyeogenolyic and gluconeogenetic effects. Due to its glycogenolytic effect on the liver, glucagon has become an established treatment of acute hypoglycaemia, including that caused by excessive insulin treatment in diabetics. In addition glucagon is known to exert a spasmolytic effect on smooth muscles which can also be exploited for therapeutic or diagnostic purposes, for example in imaging procedures.
Glucagon compositions for injection are currently marketed in the form of lyophilised powders for reconstitution with an aqueous medium, at a pH of 2-3, shortly before administration. It would be far more convenient in an emergency situation if glucagon could be provided in the form of an aqueous preparation such as an aqueous solution or aqueous gel, ready for immediate administration. Unfortunately hitherto attempts to develop such a formulation have foundered due to lack of solubility and instability of glucagon. A number of stability aspects affect glucagon in aqueous solutions, including aggregation, fibril formation and gel formation. In addition, glucagon undergoes deamidation of glutamine residues, particularly at and below pH 4 and at and above pH 7. Solubility of glucagon is generally improved at very low pH (pH<3). However, in such acidic compositions hydrolytic processes affect the stability of glucagon and such formulations also cause more pain on injection.
Nevertheless various aqueous formulations of glucagon have been proposed in the prior art.
GB1202607 claims a stable aqueous injectable glucagon solution which comprises glucagon in an amount of from 0.1 to 5 mg per ml together with a stabilising and solubilising amount of a surfactant. Anionic and cationic surfactants are described as being potentially suitable, and amongst cationic surfactants, quarternary ammonium bases in which at least one substituent is an aliphatic chain having at least 6 carbon atoms, preferably 12 to 20 carbon atoms, are preferred, especially cetrimide (cetyl trimethylammonium bromide).
WO99/47160 claims an aqueous glucagon solution comprising a stabilising and solubilising amount of a detergent having at least 2 positive charges, at least 2 negative charges, or a combination of at least one positive charge and one negative charge, the peptide being present in a concentration of at least about 0.1 mg/ml and with the proviso that the detergent is not dodecyl phosphocholine.
EP199992A1 (Eisai) describes use of benzethonium chloride and benzalkonium chloride in peptide compositions to prevent peptide adsorption onto plastic or glass. Although glucagon in mentioned in this context in very general terms in the description section, there is no working example with glucagon.
WO2011049713A2 (Biodel) discloses a stabilised glucagon formulation containing a surfactant, a mono or disaccharide, wherein the surfactant and saccharide are in an effective amount to staibilise the glucagon and wherein the osmolarity is approximately 200 to 400 mOs and the pH is between 2 and 8.
So far as we are aware none of these formulations has reached the marketplace.
We have now invented a novel glucagon formulation with a view to eliminating or mitigating some or all of the disadvantages of prior art formulations.
An objective of the invention is the provision of a formulation of glucagon which is adequately stable over a time period in storage or when carried by the patient in readiness for emergency use. Another objective of the invention is the provision of a formulation of glucagon which is adequately stable over a time period in storage and used in the prevention of hypoglycaemia or otherwise in the effective control of diabetes when administered to a patient also receiving treatment with insulin or an analogue of insulin.